Folic acid deficiency is second to iron-deficiency as a world-wide cause of nutritional anemia. In this country, folic acid deficiency is the most commonly diagnosed vitamin deficiency and is a particular problem in patients with gastrointestinal disease, in alcoholics, in patients on certain drugs and in pregnancy. Our previous efforts to understand the pathogenesis and thereby the prevention of folate deficiency have focused on the digestion and absorption of dietary polyglutamyl folates. We propose now to extend our physiological studies to the mechanism of transport of monoglutamyl folates especially the natural reduced and substituted forms. Our in vivo studies with synthetic radiolabeled substrates will lead to characterization of transport in vitro with particular use of brush border membrane vesicles. Our previous studies of specific folate binding proteins in intestinal and kidney brush border membranes will form the basis for evaluation of their role in specific "carrier-mediated" transport process. Within this framework, the mechanism by which drugs such as iphenylhydantoin, sulfasalazine, alcohol, and possibly oral contraceptives lead to folate deficiency will be investigated. Clinical studies of drug effects on folate utilization will be carried out using deuterium labeled folate with requisite isotope developed in techniques (affinity chromatography, chemical cleavage, high pressure liquid chromatography, gas chromatography-mass spectroscopy) already validated in our laboratories.